Ocean circulation, ice shelf, and sea ice interactions explain Dansgaard–Oeschger cycles
Niklas Boers, Michael Ghil, and Denis-Didier Rousseau
Paleoclimatic proxy records from Greenland ice cores show that the last glacial interval was punctuated by abrupt climatic transitions called Dansgaard–Oeschger (DO) events. These events are characterized by temperature increases over Greenland of up to 15° C within a few decades. The cause of these transitions and their out-of-phase relationship with corresponding records from Antarctica remains unclear. Based on earlier hypotheses, we propose a model focusing on interactions between ice shelves, sea ice, and ocean currents to explain DO events in Greenland and their Antarctic counterparts. Our model reproduces the main features of the observations. Our study provides a potential explanation of DO events and could help assess more accurately the risk of abrupt climatic transitions in the future. (See pp. E11005–E11014.)
A flexible organic reflectance oximeter array
Yasser Khan, Donggeon Han, Adrien Pierre, Jonathan Ting, Xingchun Wang, Claire M. Lochner, Gianluca Bovo, Nir Yaacobi-Gross, Chris Newsome, Richard Wilson, and Ana C. Arias
The optical method to determine oxygen saturation in blood is limited to only tissues that can be transilluminated. The status quo provides a single-point measurement and lacks 2D oxygenation mapping capability. We use organic printed optoelectronics in a flexible array configuration that senses reflected light from tissue. Our reflectance oximeter is used beyond conventional sensing locations and accurately measures oxygen saturation on the forehead. In a full system implementation, coupled with a mathematical model, we create 2D oxygenation maps of adult forearms under pressure-cuff–induced ischemia. Our skin-like flexible sensor system has the potential to transform oxygenation monitoring of tissues, wounds, skin grafts, and transplanted organs. (See pp. E11015–E11024.)
Engineering the protein secretory pathway of Saccharomyces cerevisiae enables improved protein production
Mingtao Huang, Guokun Wang, Jiufu Qin, Dina Petranovic, and Jens Nielsen
Recombinant proteins production by cell factories for medical and industrial use is one of the most prominent achievements in the modern biotech industry. It is constantly necessary to explore the underlying mechanisms of protein secretion to identify new targets for design and construction of improved cell factories. Here, we identified several gene targets, most of which are involved in the trafficking and secretory pathways, that could improve protein production by Saccharomyces cerevisiae to the gram per liter level. We also found that intracellular retention of recombinant proteins can be significantly reduced by engineering the endosome-to-Golgi trafficking. Genes and pathways identified here may provide general guidelines for engineering other cell factories for efficient protein secretion. (See pp. E11025–E11032.)
Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex
Alexandre Berthier, Manjula Vinod, Geoffrey Porez, Agata Steenackers, Jérémy Alexandre, Nao Yamakawa, Céline Gheeraert, Maheul Ploton, Xavier Maréchal, Julie Dubois-Chevalier, Agnès Hovasse, Christine Schaeffer-Reiss, Sarah Cianférani, Christian Rolando, Fabrice Bray, Hélène Duez, Jérôme Eeckhoute, Tony Lefebvre, Bart Staels, and Philippe Lefebvre
Using an interactomic approach, we have identified the nuclear receptor REV-ERBα as a O-GlcNAc transferase (OGT) protein partner. REV-ERBα protects cytoplasmic OGT from proteasomal degradation and facilitates cytosolic and nuclear protein O-GlcNAcylation while REV-ERα ligands decreased cytoplasmic OGT activity. REV-ERBα thus exerts pleiotropic activities through OGT, coordinating signal transduction, epigenomic programming, and transcriptional response in the liver. (See pp. E11033–E11042.)
Coupled molecular dynamics mediate long- and short-range epistasis between mutations that affect stability and aggregation kinetics
Haoran Yu and Paul A. Dalby
Incomplete understanding of the mechanisms of epistasis between two or more substitutions in a protein can hamper protein-engineering strategies. With Escherichia coli transketolase as a model, we explore the epistatic interactions between a set of stabilizing mutations from across two different domains within the protein structure. Surprisingly, not all pairwise effects between distant mutations from the surface and core regions of different domains were additive. Additionally, the epistatic behaviors observed were dependent on the type of stability measured. We found single mutations that altered local protein dynamics, which then induced correlated changes in the dynamics of a second domain of the same monomer. This mechanism mediated epistasis between distant mutations. (See pp. E11043–E11052.)
Evolution of weak cooperative interactions for biological specificity
Ang Gao, Krishna Shrinivas, Paul Lepeudry, Hiroshi I. Suzuki, Phillip A. Sharp, and Arup K. Chakraborty
Functional specificity in biology is mediated by two classes of mechanisms, “lock–key” interactions and multivalent weak cooperative interactions (WCI). Despite growing evidence that WCI are widely prevalent in higher organisms, little is known about the selection forces that drove its evolution and repeated positive selection for mediating biological specificity in metazoa. We report that multivalent WCI for mediating biological specificity evolved as the number of tasks that organisms had to perform with functional specificity became large (e.g., multicellular organisms). We find that the evolution of multivalent WCI confer enhanced and robust evolvability to organisms, and thus it has been repeatedly positively selected. Thus, we provide insights on the evolution of WCI and, more broadly, on the evolution of evolvability. (See pp. E11053–E11060.)
Polypyrimidine tract-binding protein blocks miRNA-124 biogenesis to enforce its neuronal-specific expression in the mouse
Kyu-Hyeon Yeom, Simon Mitchell, Anthony J. Linares, Sika Zheng, Chia-Ho Lin, Xiao-Jun Wang, Alexander Hoffmann, and Douglas L. Black
MicroRNAs repress genes controlling important decisions in animal development, but miRNA production and their interaction with larger genetic programs of development are not well understood. We found that the initial transcript of an important neuronal miRNA, miR-124, is expressed much earlier in development than the mature functional miRNA. Conversion of this primary RNA into its active form is blocked by the RNA binding protein PTBP1, whose down-regulation upon neuronal differentiation allows mature miR-124 expression. To understand the need for this regulation, we developed a mathematical model of the PTBP1/miR-124 regulatory circuit, finding that early expression of unprocessed miR-124 creates a sharp transition in gene expression during neuronal differentiation, making this developmental decision less affected by random variation and noise. (See pp. E11061–E11070.)
Silencing of retrotransposon-derived imprinted gene RTL1 is the main cause for postimplantational failures in mammalian cloning
Dawei Yu, Jing Wang, Huiying Zou, Tao Feng, Lei Chen, Jia Li, Xiaolan Qi, Zhifang Li, Xiaoyue Duan, Chunlong Xu, Liang Zhang, Xi Long, Jing Lan, Chao Chen, Chao Wang, Xinyu Xu, Jilong Ren, Yiqiang Zhao, Xiaoxiang Hu, Zhengxing Lian, Hongsheng Men, Dengke Pan, Ning Li, Mario R. Capecchi, Xuguang Du, Yaofeng Zhao, and Sen Wu
To investigate the epigenetic mechanism of pregnancy failure in mammals, we exploited the high rate of fetal loss in pig induced pluripotent stem cell (iPSC) nuclear transfer. We generated methylomes of pig iPSCs and associated nuclear transfer embryos from reciprocal crosses between two distinct pig breeds. Our methylome analysis revealed that misregulation of RTL1 as the principal basis of pregnancy failure using pig iPSCs. Remarkably, RTL1 has broad fertility implications across mouse, rat, pig, cattle, and human from nuclear transfer cloning, tetraploid complementation, and artificial insemination, to natural fertilization. In all of these procedures, low RTL1 expression consistently corresponds to pregnancy failures. (See pp. E11071–E11080.)
Behavior-dependent cis regulation reveals genes and pathways associated with bower building in cichlid fishes
Ryan A. York, Chinar Patil, Kawther Abdilleh, Zachary V. Johnson, Matthew A. Conte, Martin J. Genner, Patrick T. McGrath, Hunter B. Fraser, Russell D. Fernald, and J. Todd Streelman
We do not fully understand how behavior evolves. Here we investigate the genomic basis of bower building among Lake Malawi cichlid fishes. Males construct bowers of two major types, pits and castles, to attract females in mating displays. Thousands of genetic variants are strongly associated with divergence in bower behavior. Remarkably, F1 hybrids of pit-digging and castle-building species perform sequential construction of first pit and then castle bowers. Analysis of brain gene expression in hybrids showed behavior-dependent allele-specific expression with preferential expression of pit-digging alleles during pit digging and castle-building alleles during castle building. Our results suggest that behaviors evolve via complex genetic architectures featuring cis-regulatory differences whose effects on gene expression are specific and context dependent. (See pp. E11081–E11090.)
Human-like hyperplastic prostate with low ZIP1 induced solely by Zn deficiency in rats
Louise Y. Fong, Ruiyan Jing, Karl J. Smalley, Zi-Xuan Wang, Cristian Taccioli, Sili Fan, Hongping Chen, Hansjuerg Alder, Kay Huebner, John L. Farber, Oliver Fiehn, and Carlo M. Croce
Prostate cancer in man is associated with Zn loss, citrate metabolite reduction, overexpression of the miR-183-96-182 cluster, and regulation of Zn homeostasis through Zn transporter suppression. Our mechanistic study shows that a low-Zn diet upregulates this miR cluster in Zn-deficient middle-aged rat prostate, with ZIP1 mRNA/protein downregulation and a citrate-oxidizing metabolic phenotype, linking citrate reduction directly to prostatic Zn loss. The findings of this study show that the transcriptional and metabolic signal pathways induced by Zn deficiency in rats and almost certainly in men are critical for the development of human and rat prostate cancer and provide a strong rationale for including Zn supplementation in clinical trials to reduce the prostate cancer burden in the human population. (See pp. E11091–E11100.)
Criticality in tumor evolution and clinical outcome
Erez Persi, Yuri I. Wolf, Mark D. M. Leiserson, Eugene V. Koonin, and Eytan Ruppin
How mutation and selection co-determine the course of cancer evolution remains an open, fundamental question. We construct a mutation-selection phase diagram, using tumor mutation load (ML) and selection strength (dN/dS) as key variables, and assess their association with clinical outcome. The results reveal a biphasic evolutionary regime whereby beyond a critical ML, tumor fitness decreases with the number of mutations, although the proteome evolves near neutrality—that is, without strong selection. Deviations from neutrality at extreme ML show how positive selection (at low ML) and purifying selection (at high ML) may act to maintain tumor fitness. These results corroborate the existence of a critical state in cancer evolution predicted by theory and have fundamental and likely clinical implications. (See pp. E11101–E11110.)
Protective immunity in recurrent Staphylococcus aureus infection reflects localized immune signatures and macrophage-conferred memory
Liana C. Chan, Maura Rossetti, Lloyd S. Miller, Scott G. Filler, Colin W. Johnson, Hong K. Lee, Huiyuan Wang, David Gjertson, Vance G. Fowler Jr., Elaine F. Reed, Michael R. Yeaman, and the MRSA Systems Immunobiology Group
Staphylococcus aureus (SA) is the leading cause of skin and skin structure infections (SSSI), which are the main portal of entry for life-threatening invasive infections. Treatment failures are increasingly common due to antibiotic resistance. Importantly, SA SSSI exhibit high 1-year recurrence, despite high antibody levels against staphylococcal antigens. Therefore, critical determinants of immune protection against recurrent SA SSSI are not well understood. The present study offers important insights in this area, including: (i) macrophages can confer protective memory transferrable to naïve hosts; (ii) SA SSSI can induce memory in bone marrow myeloid precursors; and (iii) specific memory against recurring SA SSSI is localized and distinct from disseminated infection. These findings will accelerate novel strategies to prevent and treat SA infections. (See pp. E11111–E11119.)
Expression of ABCA4 in the retinal pigment epithelium and its implications for Stargardt macular degeneration
Tamara L. Lenis, Jane Hu, Sze Yin Ng, Zhichun Jiang, Shanta Sarfare, Marcia B. Lloyd, Nicholas J. Esposito, William Samuel, Cynthia Jaworski, Dean Bok, Silvia C. Finnemann, Monte J. Radeke, T. Michael Redmond, Gabriel H. Travis, and Roxana A. Radu
Recessive Stargardt macular degeneration (STGD1) and a subset of cone–rod dystrophies are caused by mutations in the Abca4 gene. The ABCA4 protein is a flippase in photoreceptor cells that helps eliminate retinaldehyde, a toxic photoproduct of vision. Here we found that ABCA4 is additionally present in the retinal pigment epithelium (RPE) of mice at approximately 1% of its abundance in the neural retina. Genetically modified mice that express ABCA4 in RPE but not in photoreceptor cells showed partial rescue of both the lipofuscin accumulation and photoreceptor degeneration observed in Abca4−/− mice and in STGD1 patients. These observations suggest that ABCA4 in the RPE prevents photoreceptor degeneration in Abca4−/− mice and possibly in STGD1 patients. (See pp. E11120–E11127.)
Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism
Huensuk Kim, Seungyeul Yoo, Ruoji Zhou, An Xu, Jeffrey M. Bernitz, Ye Yuan, Andreia M. Gomes, Michael G. Daniel, Jie Su, Elizabeth G. Demicco, Jun Zhu, Kateri A. Moore, Dung-Fang Lee, Ihor R. Lemischka, and Christoph Schaniel
Li–Fraumeni syndrome is a rare disorder caused by germline TP53 mutations, predisposing patients to early-onset cancers, including osteosarcoma (OS). Here we demonstrate that strong expression of SFRP2, a reported WNT antagonist, in OS patient samples correlates with poor survival and that SFRP2 overexpression suppresses normal osteoblast differentiation, promotes OS features, and facilitates angiogenesis via autocrine and paracrine mechanisms in an induced pluripotent stem cell disease model. We show that these SFRP2-mediated phenotypes are canonical WNT/β-catenin independent and are mediated through induction of oncogenes such as FOXM1 and CYR61. We further demonstrate that inhibition of SFRP2, FOXM1, or CYR61 represses tumorigenesis. Our data suggest that inhibition of SFRP2 should be explored clinically as a strategy for treatment patients with p53 mutation-associated OS. (See pp. E11128–E11137.)
Vorinostat, a pan-HDAC inhibitor, abrogates productive HPV-18 DNA amplification
N. Sanjib Banerjee, Dianne W. Moore, Thomas R. Broker, and Louise T. Chow
Persistent infection by the high-risk human papillomaviruses (HPVs) can lead to anogenital and head and neck cancers. The HPV vaccines effectively prevent new type-restricted infections but have no effect on preexisting infections. It is crucial to identify effective inhibitors of preneoplastic HPV infections. Histone deacetylases (HDACs) modulate chromatin structure and transcription, and are also essential for chromatin replication fork progression. Here we show that Vorinostat, a pan-HDAC inhibitor, stabilizes host cell tumor suppressors targeted by HPV oncoproteins E6 and E7 and abrogates productive infection by a high-risk HPV in organotypic cultures of human keratinocytes. Furthermore, Vorinostat selectively induces apoptosis in HPV-infected cells by decreasing DNA repair response while increasing the proapoptotic protein Bim. Vorinostat appears to be a promising therapeutic agent. (See pp. E11138–E11147.)
Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model
Karolina J. Janczura, Claude-Henry Volmar, Gregory C. Sartor, Sunil J. Rao, Natalie R. Ricciardi, Guerline Lambert, Shaun P. Brothers, and Claes Wahlestedt
With the imminent increase of the elderly population worldwide, Alzheimer’s disease (AD) is one of the most significant medical problems in modern society. Although nonselective histone deacetylase (HDAC) proteins delineate a promising druggable target and nonselective HDAC inhibitors have been shown effective for other indications, they present a wide spectrum of side-effects. Selective inhibition of HDAC isoforms may, however, greatly eliminate such toxicities while presenting improved efficacy. We demonstrate that RGFP-966, a selective HDAC3 inhibitor, decreases accumulation of proteins relevant for AD pathophysiology and alleviates memory impairment in an AD mouse model. The presented work provides evidence for a crucial role of HDAC3 in mediating AD-like pathology and opens an avenue for the discovery of epigenetic therapeutics for AD. (See pp. E11148–E11157.)
Face cells in orbitofrontal cortex represent social categories
Elodie Barat, Sylvia Wirth, and Jean-René Duhamel
We show that the orbitofrontal cortex contains cells that first discriminate face from nonface stimuli, then categorize faces by their intrinsic sociodemographic and emotional content. In view of the role of the orbitofrontal cortex in reward processing, decision making, and social behavior, our detailed characterization of these cells sheds light on mechanisms by which of social categories are represented in this region. These data articulate a more comprehensive view of the neural architecture for processing face information, one including areas far beyond the core occipitotemporal regions. (See pp. E11158–E11167.)
Autocrine signaling by an Aplysia neurotrophin forms a presynaptic positive feedback loop
Iksung Jin, Hiroshi Udo, Russell Nicholls, Huixiang Zhu, Eric R. Kandel, and Robert D. Hawkins
Whereas short-term plasticity is often initiated on one side of the synapse, long-term plasticity involves coordinated changes on both sides, implying extracellular signaling. We have investigated the possible signaling role of an Aplysia neurotrophin (ApNT) and found that it acts as a presynaptic autocrine signal, which forms part of a positive feedback loop that drives consolidation of learning-related synaptic plasticity. (See pp. E11168–E11177.)
Arabidopsis thaliana NGATHA1 transcription factor induces ABA biosynthesis by activating NCED3 gene during dehydration stress
Hikaru Sato, Hironori Takasaki, Fuminori Takahashi, Takamasa Suzuki, Satoshi Iuchi, Nobutaka Mitsuda, Masaru Ohme-Takagi, Miho Ikeda, Mitsunori Seo, Kazuko Yamaguchi-Shinozaki, and Kazuo Shinozaki
The plant hormone abscisic acid (ABA) is essential for drought-stress responses in plants, and its functions have been well studied; however, the detailed molecular mechanisms of ABA biosynthesis during early drought stress need to be further explored. The present study identified a transcription factor, NGTHA1 (NGA1), which positively regulates ABA accumulation during dehydration stress by activating the NCED3 gene encoding a key ABA biosynthetic enzyme. We also identified a cis-acting element bound by NGA1 in the 5′ untranslated region (5′ UTR) of the NCED3 promoter. The NGA1 protein was degraded under nonstressed conditions, but it was stabilized during dehydration stress in an ABA-independent pathway. (See pp. E11178–E11187.)
Flavonols control pollen tube growth and integrity by regulating ROS homeostasis during high-temperature stress
Joëlle K. Muhlemann, Trenton L. B. Younts, and Gloria K. Muday
Plant sexual reproduction is required for seed and fruit production and is highly sensitive to elevated temperatures, suggesting that climate change may have profound agricultural impacts through inhibition of this process. During reproduction, pollen tubes must navigate long distances through floral tissues to fertilize ovules. We demonstrate that high-temperature stress increases levels of reactive oxygen species in pollen tubes, which inhibits pollen tube growth. We report that specialized metabolites of the flavonol class prevent reactive oxygen species from reaching inhibitory levels at normal and increased temperatures, thereby promoting pollen viability and pollen tube growth. These results indicate that flavonols enhance reproduction, particularly during heat stress, and could confer protection to plants against the negative effects of climate change. (See pp. E11188–E11197.)